Roughly 50% of patients with breast cancer are classified with human epidermal growth factor receptor 2 (HER2)-low expression on the basis of their immunohistochemistry (IHC) and/or in situ hybridization (ISH) findings (ie, IHC 1+ or IHC 2+/ISH–). The historically poor responses to HER2-targeted therapies by this group of patients results in their inclusion in the larger HER2-negative category on the pathology reports used by medical oncologists to determine treatment. HER2-low breast cancers may be either hormone receptor (HR) positive or HR negative, varying in prognosis and sensitivity to standard therapies. Overall, patients with relapsed/refractory HER2-low breast cancers have limited targeted treatment options and typically receive single-agent palliative chemotherapy.
Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) approved in the US and Europe in the second quarter of 2022 for HER2-positive breast cancer on the basis of results from the DESTINY-Breast03 trial. Recently, Dr Shanu Modi and colleagues published results from DESTINY-Breast04, a randomized, 2-group, open-label, phase III trial that evaluated the efficacy and safety of trastuzumab deruxtecan compared with chemotherapy in patients with HER2-low metastatic breast cancer. Three hundred seventy-three patients were randomly assigned to receive trastuzumab deruxtecan and 184 were assigned the physician’s choice, which was eribulin, capecitabine, nab-paclitaxel, gemcitabine, or paclitaxel. The majority of patients in both groups were HR positive.
In DESTINY-Breast04, trastuzumab deruxtecan successfully prolonged both progression-free survival (PFS) and overall survival (OS) among patients categorized as having HER2-low unresectable and/or metastatic breast cancer, compared with physician’s choice of standard single-agent chemotherapy. Among the HR-positive subgroup, those treated with trastuzumab deruxtecan had significantly longer PFS and OS than those who received physician’s choice of chemotherapy. At the time of data cutoff, median PFS in HR-positive patients was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group. Benefits were consistent across analyzed subgroups, including among those with and without previous cyclin-dependent kinase 4/6 inhibitor treatment. Similarly, among the entire cohort, median PFS was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group. PFS was lower among HR-negative patients: 8.5 months with trastuzumab deruxtecan and 2.9 months with the physician’s choice treatment. Median OS was also higher in HR-positive patients, at just under 2 years in the trastuzumab deruxtecan group and 17.5 months in the physician’s choice group. In the full study population, median OS was 23.4 months in the trastuzumab deruxtecan group and 16.8 months in the physician’s choice group. Confirmed objective response was achieved in more than half (52.6%) of patients in the trastuzumab deruxtecan group (vs 16.3% in the physician’s choice group), with a 10.7-month median duration of response.
The safety profile of trastuzumab deruxtecan was similar to the established safety profile in patients with HER2-positive metastatic breast cancer. The incidence of serious adverse events was similar between groups: 27.8% in the trastuzumab deruxtecan group and 25.0% in the physician’s choice group. There were more adverse events associated with treatment discontinuation in the trastuzumab deruxtecan arm. The most common drug-related adverse events in patients receiving trastuzumab deruxtecan were nausea, fatigue, and alopecia. Consistent with previous studies, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients who received trastuzumab deruxtecan and were mostly mild or moderate. Median time to onset of these events was 129 days.
Overall, the authors concluded that targeting low levels of HER2 with trastuzumab deruxtecan was superior to untargeted chemotherapy in patients with HER2-low metastatic breast cancer. Regardless of HR status, risk of disease progression or death was approximately 50% lower with trastuzumab deruxtecan.
The results of this trial have the potential to improve treatment outcomes for more than half of patients who were historically categorized as having HER2-negative breast cancer. The study highlights the clinical relevance of the HER2-low patient population and supports a need to redefine subgroups within HER2-negative breast cancers. Protocols should include a conventional IHC analysis to accurately identify patients who are HER2 low and may benefit from trastuzumab deruxtecan. Additional trials are still needed to further understand the appropriate use of ADCs in this patient population. The authors suggest that because the HER2-low population includes both HR-positive and HR-negative subgroups of patients, trials in these populations can serve as a comparison for this new subgroup.
These results suggest that HER2 overexpression may not be required for new ADCs to be effective. Trastuzumab deruxtecan offers another unique targeted-therapy option for HER2-low patients, an otherwise poor-prognosis patient group. A conventional IHC analysis is recommended to accurately identify patients who may benefit from trastuzumab deruxtecan. As the safety profile is similar to that of patients with HER2-positive metastatic breast cancer, interstitial lung disease or pneumonitis remain important risks that should be monitored and managed with prompt dose interruption and early institution of glucocorticoid treatment.